CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Gehin C, Lone MA, Lee W, Capolupo L, Ho S, Adeyemi AM, Gerkes EH, Stegmann AP, López-Martín E, Bermejo-Sánchez E, Martínez-Delgado B, Zweier C, Kraus C, Popp B, Strehlow V, Gräfe D, Knerr I, Jones ER, Zamuner S, Abriata LA, Kunnathully V, Moeller BE, Vocat A, Rommelaere S, Bocquete JP, Ruchti E, Limoni G, Van Campenhoudt M, Bourgeat S, Henklein P, Gilissen C, van Bon BW, Pfundt R, Willemsen MH, Schieving JH, Leonardi E, Soli F, Murgia A, Guo H, Zhang Q, Xia K, Fagerberg CR, Beier CP, Larsen MJ, Valenzuela I, Fernández-Álvarez P, Xiong S, Śmigiel R, López-González V, Armengol L, Morleo M, Selicorni A, Torella A, Blyth M, Cooper NS, Wilson V, Oegema R, Herenger Y, Garde A, Bruel AL, Tran Mau-Them F, Maddocks AB, Bain JM, Bhat MA, Costain G, Kannu P, Marwaha A, Champaigne NL, Friez MJ, Richardson EB, Gowda VK, Srinivasan VM, Gupta Y, Lim TY, Sanna-Cherchi S, Lemaitre B, Yamaji T, Hanada K, Burke JE, Jakšić AM, McCabe BD, De Los Rios P, Hornemann T, D'Angelo G, Gennarino VA (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Book Volume: 133

Journal Issue: 10

DOI: 10.1172/JCI165019

Abstract

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.

Authors with CRIS profile

Involved external institutions

Universität Leipzig Germany (DE) Universitätsklinikum Leipzig Germany (DE) Genuity Science Ireland (IE) École Polytechnique Fédérale de Lausanne (EPFL) Switzerland (CH) Universitätsspital Zürich (USZ) Switzerland (CH) Maastricht University Medical Center (UMC+) Netherlands (NL) Research Institute for Rare Diseases / Instituto de Investigación de Enfermedades Raras (IIER) Spain (ES) National Centre for Inherited Metabolic Disorders (NCIMD) Ireland (IE) Consiglio Nazionale delle Ricerche (CNR) / National Research Council of Italy Italy (IT) University of Victoria (UVic) Canada (CA) Central South University China (CN) University of Calgary Canada (CA) University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen Netherlands (NL) SIB Swiss Institute of Bioinformatics / SIB Institut Suisse de Bioinformatique / SIB Istituto Svizzero di Bioinformatica / SIB Schweizerisches Institut für Bioinformatik Switzerland (CH) Freie Universität Berlin Germany (DE) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) Birmingham Women's and Children's NHS Foundation Trust United Kingdom (GB) Newcastle upon Tyne Hospitals NHS Foundation Trust United Kingdom (GB) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) Genetica AG Switzerland (CH) Centre hospitalier universitaire (CHU) de Dijon Bourgogne France (FR) Université Bourgogne Franche-Comté France (FR) Columbia University Irving Medical Center (CUIMC) United States (USA) (US) University of Zurich / Universität Zürich (UZH) Switzerland (CH) University of Alberta Canada (CA) University of Padua / Universita degli Studi di Padova Italy (IT) Azienda Provinciale per i Servizi Sanitari Italy (IT) Fondazione Istituto di Ricerca Pediatrica Città della Speranza (IRP) Italy (IT) Odense Universitetshospital (OUH) Denmark (DK) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron Spain (ES) Tongji University / 同济大学 China (CN) Ospedale Sant'Anna Italy (IT) Telethon Institute of Genetics and Medicine (TIGEM) Italy (IT) NHS Grampian United Kingdom (GB) Medical University of South Carolina (MUSC) United States (USA) (US) Indira Gandhi Institute of Child Health India (IN) Columbia University United States (USA) (US) National Institute of Infectious Diseases, Japan (NIID) Japan (JP) Wrocław Medical University / Uniwersytet Medyczny we Wrocławiu Poland (PL) Hospital Clínico Universitario Virgen de la Arrixaca Spain (ES) Quantitative Genomic Medicine Laboratories, S.L. Spain (ES) The Hospital for Sick Children (SickKids) Canada (CA)

How to cite

APA:

Gehin, C., Lone, M.A., Lee, W., Capolupo, L., Ho, S., Adeyemi, A.M.,... Gennarino, V.A. (2023). CERT1 mutations perturb human development by disrupting sphingolipid homeostasis. Journal of Clinical Investigation, 133(10). https://dx.doi.org/10.1172/JCI165019

MLA:

Gehin, Charlotte, et al. "CERT1 mutations perturb human development by disrupting sphingolipid homeostasis." Journal of Clinical Investigation 133.10 (2023).

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